Protective effect of DMPC, DMPG, DMPC/DMPG, lysoPG and lysoPC against drugs that cause channelopathies

ABSTRACT

The present invention includes compositions and methods for preventing one or more cardiac channelopathies or conditions resulting from irregularities or alterations in cardiac patterns caused by an active agent or a drug in a human or animal subject comprising: an amount of a lysophosphatidylglycerol adapted for oral administration effective to reduce or prevent one or more cardiac channelopathies or conditions resulting from irregularities or alterations in cardiac patterns caused by the active agent or drug.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part patent application of U.S.patent application Ser. No. 14/729,940 filed on Jun. 3, 2015, whichclaims priority to U.S. Provisional Application Ser. No. 62/007,244filed on Jun. 3, 2014; this application is also a continuation-in-partpatent application of U.S. patent application Ser. No. 14/575,644 filedon Dec. 18, 2014, which claims priority to U.S. Provisional ApplicationSer. No. 61/917,426 filed on Dec. 18, 2013; this application is also acontinuation-in-part application of U.S. patent application Ser. No.15/068,300 filed on Mar. 11, 2016, which is a continuation applicationthat claims priority to U.S. patent application Ser. No. 14/268,376filed on May 2, 2014, which is a continuation application that claimspriority to U.S. patent application Ser. No. 13/487,233 filed on Jun. 3,2012, now U.S. Pat. No. 8,753,674 issued on Jun. 17, 2014, which claimspriority to U.S. Provisional Application Ser. No. 61/493,257 filed onJun. 3, 2011, the entire contents of each, which are incorporated hereinby reference.

STATEMENT OF FEDERALLY FUNDED RESEARCH

None.

INCORPORATION-BY-REFERENCE OF MATERIALS FILED ON COMPACT DISC

None.

TECHNICAL FIELD OF THE INVENTION

The present invention relates in general to the field of drug treatment,and more particularly, to novel compositions and methods for reducing oreliminating channelopathies or conditions resulting from irregularitiesor alterations in cardiac patterns caused by an active agent or a drug.

BACKGROUND OF THE INVENTION

Without limiting the scope of the invention, its background is describedin connection with compositions and methods for controlling the durationof repolarization of the cardiac ventricle QT in a subject comprisingadministering to subject in need thereof of a modification of orfunctional interference with a therapeutic agent, or congenital defectwhich if unmodified can induce prolongation of repolarization in theheart myocyte action potential, torsade de points, and the long QTsyndrome.

The beating of the heart is due to precisely controlled regularly spacedwaves of myocardial excitation and contraction. The electrical currentsduring ion-based depolarization and repolarization can be measured byelectrical leads placed on the body in specific locations (theelectrocardiogram) which measure electrical waves. The P-wave representsa wave of depolarization in the atrium. When the entire atria becomesdepolarized, the wave returns to zero. After 0.1 seconds the ventricleis entirely depolarized resulting in the QRS complex. The three peaksare due to the way the current spreads in the ventricles. This isfollowed by the T-wave or repolarization of the ventricle. The QTinterval measured from the beginning of the QRS complex to the end ofthe T wave on the standard ECG represents the duration till thecompletion of the repolarization phase of the cardiac myocyte (or thedepolarization and repolarization of the ventricle). The duration ofthis interval can vary due to genetic variation, cardiac disease,electrolyte balance, envenomation, and drugs. Prolongation of the QTinterval can result in ventricular arrhythmias and sudden death.

Drug induced long QTc Syndrome (LQTS) i.e., a prolongation of the actionpotential duration is a common cause of governmental mandated drugwithdrawal. QTc prolongation is an unpredictable risk factor forTorsades de Pointes (TdP), a polymorphic ventricular tachycardia leadingto ventricular fibrillation. Drug induced LQTS comprises about 3% of allprescriptions which when followed by TdP may constitute a lethal adversereaction. Patients taking one or more than one QTc-prolonging drugconcomitantly, have an enhanced risk of TdP. While the overalloccurrence of TdP is statistically rare but clinically significant forthe affected individual, assay for this drug effect is a mandatoryrequirement prior to allowing a drug to enter clinical trials.

Common structurally diverse drugs block the human ether-a-go-go-relatedgene (KCNH2 or hERG) coded K⁺ channel and the cardiac delayed-rectifierpotassium current I_(K) (KV11.1) resulting in acquired LQTS.Drug-associated increased risk of LQTS is a major drug developmenthurdle and many drugs have been withdrawn during pre-clinicaldevelopment, or assigned black box warnings following approval orwithdrawn from the market. Autosomal recessive or dominant LQTS basedupon 500 possible mutations in 10 different genes coding for thepotassium channel has an incidence of 1:3000 or about 100,000 persons inthe US. Prolonged QT intervals, or risk of LQTS occur in 2.5% of theasymptomatic US population. This syndrome when expressed can lead tosevere cardiac arrhythmia and sudden death in untreated patients. Theprobability of cardiac death in patients with asymptomatic congenitalLQTS who are medicated with LQTS-inducing drugs is increased.

The majority of the acquired LTQS drug withdrawals are due toobstruction of the potassium ion channels coded by the humanether-a-go-go related gene (hERG). High concentrations of hERG blockingdrugs generally induce a prolonged QTc interval and increase theprobability of TdP. Up to 10% of cases of drug-induced TdP can be due todue to 13 major genetic mutations, 471 different mutations, and 124polymorphisms (Chig, C 2006).

Systems and methods for detection of LQTS have been describedpreviously. For example U.S. Patent Publication No. 2010/0004549 (Kohlset al. 2010) discloses a system and method of detecting LQTS in apatient by comparing a collected set of ECG data from the patient to aplurality of databases of collected ECG data. The plurality of databaseswill include a database containing previous ECGs from the patient, aknown acquired LQTS characteristics database, and a known genetic LQTScharacteristics database. Comparing the patient's ECG to these databaseswill facilitate the detection of such occurrences as changes in QTinterval from success of ECGs, changes in T-wave morphology, changes inU-wave morphology, and can match known genetic patterns of LQTS. Thesystem and method is sensitive to patient gender and ethnicity, as thesefactors have been shown to effect LQTS, and is furthermore capable ofmatching a QT duration to a database of drug effects. The system andmethod is also easily integrated into current ECG management systems andstorage devices.

A system and method for the diagnosis and treatment of LQTS is describedin U.S. Patent Publication No. 2008/0255464 (Michael, 2008). The Michaelinvention includes a system for diagnosing Long QT Syndrome (LQTS)derives a QT/QS2 ratio from an electrical systole (QT) and a mechanicalsystole (QS2) to detect a prolonged QT interval in a patient's cardiaccycle. A processor acquires the systoles from a microphone and chestelectrodes, calculates the QT/QS2 ratio, and outputs the result to adisplay. The processor may compare the QT/QS2 ratio to a threshold valuestored in memory for diagnosing LQTS in the patient. A user interfaceprovides for programming, set-up, and customizing the display. A modeselector allows the system to operate alternatively as aphonocardiograph, a 12 lead electrocardiograph, or a machine fordiagnosing LQTS. A related method for diagnosing cardiac disorders suchas LQTS includes measuring QT and QS2 during a same cardiac cycle,calculating a QT/QS2 ratio, and comparing the result to a thresholdvalue derived from empirical data. The method may include measuringsystoles both at rest and during exercise, and may be used for drugefficacy, dosage optimization, and acquired LQTS causality tests.

A method for the treatment of cardiac arrhythmias is provided in U.S.Patent Publication No. 2007/0048284 (Donahue and Marban, 2007). Themethod includes administering an amount of at least one polynucleotidethat modulates an electrical property of the heart. The polynucleotidesof the invention may also be used with a microdelivery vehicle such ascationic liposomes and adenoviral vectors.

Methods, compositions, dosing regimes, and routes of administration forthe treatment or prevention of arrhythmias have been described by Fedidaet al. (2010) in U.S. Patent Publication No. 2001/00120890. In theFedida invention, early after depolarizations and prolongation of QTinterval may be reduced or eliminated by administering ion channelmodulating compounds to a subject in need thereof. The ion channelmodulating compounds may be cycloalkylamine ether compounds,particularly cyclohexylamine ether compounds. Also described arecompositions of ion channel modulating compounds and drugs which induceearly after depolarizations, prolongation of QT interval and/or Torsadesde Pointes. The Fedida invention also discloses antioxidants which maybe provided in combination with the ion channel modulating compounds,non-limiting examples of the antioxidants include vitamin C, vitamin E,beta-carotene, lutein, lycopene, vitamin B2, coenzyme Q10, cysteine aswell as herbs, such as bilberry, turmeric (curcumin), grape seed or pinebark extracts, and ginkgo.

SUMMARY OF THE INVENTION

In one embodiment, the present invention includes a composition forpreventing one or more cardiac channelopathies or conditions resultingfrom irregularities or alterations in cardiac patterns caused by anactive agent or a drug in a human or animal subject comprising: anamount of a lysophosphatidylglycerol adapted for oral administrationeffective to reduce or prevent one or more cardiac channelopathies orconditions resulting from irregularities or alterations in cardiacpatterns caused by the active agent or drug. In one aspect, thelysophosphatidylglycerol includes at least one of alysophosphatidylcholine, lauroyl-lysophosphatidylcholine,myristoyl-lysophosphatidylcholine, palmitoyl-lysophosphatidylcholine,stearoyl-lysophosphatidylcholine, arachidoyl-lysophosphatidylcholine,oleoyl-lysophosphatidylcholine, linoleoyl-lysophosphatidylcholine,linolenoyl-lysophosphatidylcholine or erucoyl-lysophosphatidylcholine.In another aspect, the lysophosphatidylglycerol include at least one or1-Myristoyl-2-Hydroxy-sn-Glycero-3-Phosphocholine (DMPC),12-Mysteroyl-2-Hydroxy-sn-Glycero-3-[Phospho-rac-(glycerol)](DMPG),DMPC/DMPG, 1-myristoyl-2-hydroxy-sn-glycero-3-phospho-(1′-rac-glycerol)(LysoPG), or 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine (LysoPC).In another aspect, the lysophosphatidylglycerol is defined further as ashort chain fatty acid is up to 5 carbons, a medium chain is 6 to 12carbons, a long chain is 13-21 carbons and a very long chain fatty acidis greater than 22 carbons, including both even and odd chain fattyacids. In another aspect, the lysophosphatidylglycerol has 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 35, 40, 45, 50, 55 or more carbons, which aresaturated or unsaturated. In another aspect, the cardiac channelopathyor the condition resulting from the irregularity or alteration in thecardiac pattern is inhibition of an ion channel responsible for thedelayed-rectifier K⁺ current in the heart, polymorphic ventriculartachycardia, prolongation of the QTc, LQT2, LQTS, or torsades depointes. In another aspect, the composition is used for the treatment orprevention of prolongation of the I_(Kr) channel inhibition or QTprolongation induced by administration of the active agent or drug usedin the treatment of cardiac, allergic, or cancer related diseases. Inanother aspect, the active agent drug is selected from at least one ofcrizotinib, nilotinib, terfenadine, astemizole, gripafloxacin,terodilene, droperidole, lidoflazine, levomethadyl, sertindoyle orcisapride. In another aspect, the active agent drug is providedenterally, parenterally, intravenously, intraperitoneally, or orally. Inanother aspect, the active agent drug is provided in a liposomes andcomprises a lipid or a phospholipid wall, wherein the lipids or thephospholipids are selected from the group consisting ofphosphatidylcholine (lecithin), lysolecithin,lysophosphatidylethanol-amine, phosphatidylserine, phosphatidylinositol,sphingomyelin, phosphatidylethanolamine (cephalin), cardiolipin,phosphatidic acid, cerebrosides, dicetylphosphate, phosphatidylcholine,and dipalmitoyl-phosphatidylglycerol, stearylamine, dodecylamine,hexadecyl-amine, acetyl palmitate, glycerol ricinoleate, hexadecylsterate, isopropyl myristate, amphoteric acrylic polymers, fatty acid,fatty acid amides, cholesterol, cholesterol ester, diacylglycerol, anddiacylglycerolsuccinate. In another aspect, the drug is selected fromAlbuterol (salbutamol), Alfuzosin, Amantadine, Amiodarone, Amisulpride,Amitriptyline, Amoxapine, Amphetamine, Anagrelide, Apomorphine,Arformoterol, Aripiprazole, Arsenic trioxide, Astemizole, Atazanavir,Atomoxetine, Azithromycin, Bedaquiline, Bepridil, Bortezomib, Bosutinib,Chloral hydrate, Chloroquine, Chlorpromazine, Ciprofloxacin, Cisapride,Citalopram, Clarithromycin, Clomipramine, Clozapine, Cocaine,Crizotinib, Dabrafenib, Dasatinib, Desipramine, Dexmedetomidine,Dexmethylphenidate, Dextroamphetamine (d-Amphetamine),Dihydroartemisinin+piperaquine, Diphenhydramine, Disopyramide,Dobutamine, Dofetilide, Dolasetron, Domperidone, Dopamine, Doxepin,Dronedarone, Droperidol, Ephedrine, Epinephrine (Adrenaline), Eribulin,Erythromycin, Escitalopram, Famotidine, Felbamate, Fenfluramine,Fingolimod, Flecainide, Fluconazole, Fluoxetine, Formoterol, Foscarnet,Fosphenytoin, Furosemide (Frusemide), Galantamine, Gatifloxacin,Gemifloxacin, Granisetron, Halofantrine, Haloperidol,Hydrochlorothiazide, Ibutilide, Iloperidone, Imipramine (melipramine),Indapamide, Isoproterenol, Isradipine, Itraconazole, Ivabradine,Ketoconazole, Lapatinib, Levalbuterol (levsalbutamol), Levofloxacin,Levomethadyl, Lisdexamfetamine, Lithium, Mesoridazine, Metaproterenol,Methadone, Methamphetamine (methamfetamine), Methylphenidate, Midodrine,Mifepristone, Mirabegron, Mirtazapine, Moexipril/HCTZ, Moxifloxacin,Nelfinavir, Nicardipine, Nilotinib, Norepinephrine (noradrenaline),Norfloxacin, Nortriptyline, Ofloxacin, Olanzapine, Ondansetron,Oxytocin, Paliperidone, Paroxetine, Pasireotide, Pazopanib, Pentamidine,Perflutren lipid microspheres, Phentermine, Phenylephrine,Phenylpropanolamine, Pimozide, Posaconazole, Probucol, Procainamide,Promethazine, Protriptyline, Pseudoephedrine, Quetiapine, Quinidine,Quinine sulfate, Ranolazine, Rilpivirine, Risperidone, Ritodrine,Ritonavir, Roxithromycin, Salmeterol, Saquinavir, Sertindole,Sertraline, Sevoflurane, Sibutramine, Solifenacin, Sorafenib, Sotalol,Sparfloxacin, Sulpiride, Sunitinib, Tacrolimus, Tamoxifen, Telaprevir,Telavancin, Telithromycin, Terbutaline, Terfenadine, Tetrabenazine,Thioridazine, Tizanidine, Tolterodine, Toremifene, Trazodone,Trimethoprim-Sulfa, Trimipramine, Vandetanib, Vardenafil, Vemurafenib,Venlafaxine, Voriconazole, Vorinostat, or Ziprasidone.

In one embodiment, the present invention includes a composition forpreventing or treating diseases with an active agent or drug that causesone or more adverse reactions arising from administration of an activeagent or drug in a human that causes at least one of cardiacchannelopathies, I_(Kr) channel inhibition or QT prolongationcomprising:

an amount of a lysophosphatidylglycerol with a basic structure:

wherein R¹ or R² can be any even or odd-chain fatty acid, and R³ can beH, acyl, alkyl, aryl, amino acid, alkenes, alkynes, adapted for oraladministration effective to reduce or prevent the at least one cardiacchannelopathies, I_(Kr) channel inhibition or QT prolongation caused bythe drug; and one or more active agents or drugs that cause at least oneof I_(Kr) channel inhibition or QT prolongation. In one aspect, thelysophosphatidylglycerol includes at least one of alysophosphatidylcholine, lauroyl-lysophosphatidylcholine,myristoyl-lysophosphatidylcholine, palmitoyl-lysophosphatidylcholine,stearoyl-lysophosphatidylcholine, arachidoyl-lysophosphatidylcholine,oleoyl-lysophosphatidylcholine, linoleoyl-lysophosphatidylcholine,linolenoyl-lysophosphatidylcholine or erucoyl-lysophosphatidylcholine.In another aspect, the liposome or liposome precursors are selected fromat least one or 1-Myristoyl-2-Hydroxy-sn-Glycero-3-Phosphocholine(DMPC), 12-Mysteroyl-2-Hydroxy-sn-Glycero-3-[Phospho-rac-(glycerol)](DMPG), DMPC/DMPG,1-myristoyl-2-hydroxy-sn-glycero-3-phospho-(1′-rac-glycerol) (LysoPG),or 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine (LysoPC). Inanother aspect, the short chain fatty acid is up to 5 carbons, a mediumchain is 6 to 12 carbons, a long chain is 13-21 carbons and a very longchain fatty acid is greater than 22 carbons, including both even and oddchain fatty acids. In another aspect, the short chain fatty acid has 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55 or more carbons,which are saturated or unsaturated. In another aspect, the cardiacchannelopathy or the condition resulting from the irregularity oralteration in the cardiac pattern is inhibition of an ion channelresponsible for the delayed-rectifier K⁺ current in the heart,polymorphic ventricular tachycardia, prolongation of the QTc, LQT2,LQTS, or torsades de pointes. In another aspect, the composition is usedfor the treatment or prevention of prolongation of the I_(Kr) channelinhibition or QT prolongation induced by administration of one or moredrugs used in the treatment of cardiac, allergic, or cancer relateddisease. In another aspect, the one or more active agents is selectedfrom at least one of crizotinib, nilotinib, terfenadine, astemizole,gripafloxacin, terodilene, droperidole, lidoflazine, levomethadyl,sertindoyle or cisapride. In another aspect, the active agent or drug isprovided enterally, parenterally, intravenously, intraperitoneally, ororally. In another aspect, the liposomes comprises a lipid or aphospholipid wall, wherein the lipids or the phospholipids are selectedfrom the group consisting of phosphatidylcholine (lecithin),lysolecithin, lysophosphatidylethanol-amine, phosphatidylserine,phosphatidylinositol, sphingomyelin, phosphatidylethanolamine(cephalin), cardiolipin, phosphatidic acid, cerebrosides,dicetylphosphate, phosphatidylcholine, anddipalmitoyl-phosphatidylglycerol, stearylamine, dodecylamine,hexadecyl-amine, acetyl palmitate, glycerol ricinoleate, hexadecylsterate, isopropyl myristate, amphoteric acrylic polymers, fatty acid,fatty acid amides, cholesterol, cholesterol ester, diacylglycerol, anddiacylglycerolsuccinate. In another aspect, the drug is selected fromAlbuterol (salbutamol), Alfuzosin, Amantadine, Amiodarone, Amisulpride,Amitriptyline, Amoxapine, Amphetamine, Anagrelide, Apomorphine,Arformoterol, Aripiprazole, Arsenic trioxide, Astemizole, Atazanavir,Atomoxetine, Azithromycin, Bedaquiline, Bepridil, Bortezomib, Bosutinib,Chloral hydrate, Chloroquine, Chlorpromazine, Ciprofloxacin, Cisapride,Citalopram, Clarithromycin, Clomipramine, Clozapine, Cocaine,Crizotinib, Dabrafenib, Dasatinib, Desipramine, Dexmedetomidine,Dexmethylphenidate, Dextroamphetamine (d-Amphetamine),Dihydroartemisinin+piperaquine, Diphenhydramine, Disopyramide,Dobutamine, Dofetilide, Dolasetron, Domperidone, Dopamine, Doxepin,Dronedarone, Droperidol, Ephedrine, Epinephrine (Adrenaline), Eribulin,Erythromycin, Escitalopram, Famotidine, Felbamate, Fenfluramine,Fingolimod, Flecainide, Fluconazole, Fluoxetine, Formoterol, Foscarnet,Fosphenytoin, Furosemide (Frusemide), Galantamine, Gatifloxacin,Gemifloxacin, Granisetron, Halofantrine, Haloperidol,Hydrochlorothiazide, Ibutilide, Iloperidone, Imipramine (melipramine),Indapamide, Isoproterenol, Isradipine, Itraconazole, Ivabradine,Ketoconazole, Lapatinib, Levalbuterol (levsalbutamol), Levofloxacin,Levomethadyl, Lisdexamfetamine, Lithium, Mesoridazine, Metaproterenol,Methadone, Methamphetamine (methamfetamine), Methylphenidate, Midodrine,Mifepristone, Mirabegron, Mirtazapine, Moexipril/HCTZ, Moxifloxacin,Nelfinavir, Nicardipine, Nilotinib, Norepinephrine (noradrenaline),Norfloxacin, Nortriptyline, Ofloxacin, Olanzapine, Ondansetron,Oxytocin, Paliperidone, Paroxetine, Pasireotide, Pazopanib, Pentamidine,Perflutren lipid microspheres, Phentermine, Phenylephrine,Phenylpropanolamine, Pimozide, Posaconazole, Probucol, Procainamide,Promethazine, Protriptyline, Pseudoephedrine, Quetiapine, Quinidine,Quinine sulfate, Ranolazine, Rilpivirine, Risperidone, Ritodrine,Ritonavir, Roxithromycin, Salmeterol, Saquinavir, Sertindole,Sertraline, Sevoflurane, Sibutramine, Solifenacin, Sorafenib, Sotalol,Sparfloxacin, Sulpiride, Sunitinib, Tacrolimus, Tamoxifen, Telaprevir,Telavancin, Telithromycin, Terbutaline, Terfenadine, Tetrabenazine,Thioridazine, Tizanidine, Tolterodine, Toremifene, Trazodone,Trimethoprim-Sulfa, Trimipramine, Vandetanib, Vardenafil, Vemurafenib,Venlafaxine, Voriconazole, Vorinostat, or Ziprasidone.

In one embodiment, the present invention includes a method forpreventing or treating one or more cardiac channelopathies,irregularities or alterations in cardiac patterns, I_(Kr) channelinhibition or QT prolongation, in a human or animal subject caused by anactive agent or drug, wherein the active agents or drugs are used totreat a disease in a human or animal subject comprising the steps of:administering to the human or animal subject an amount of alysophosphatidylglycerol adapted for oral administration effective toreduce or prevent one or cardiac channelopathies, irregularities oralterations in cardiac patterns, I_(Kr) channel inhibition, or QTprolongation caused by the active agent or drug; and an effective amountof the active agent or drug sufficient to treat the disease, wherein theorally provided lysophosphatidylglycerol reduces or eliminates the atleast one cardiac channelopathies, irregularities or alterations incardiac patterns, I_(Kr) channel inhibition or QT prolongation. In oneaspect, the lysophosphatidylglycerol includes at least one of alysophosphatidylcholine, lauroyl-lysophosphatidylcholine,myristoyl-lysophosphatidylcholine, palmitoyl-lysophosphatidylcholine,stearoyl-lysophosphatidylcholine, arachidoyl-lysophosphatidylcholine,oleoyl-lysophosphatidylcholine, linoleoyl-lysophosphatidylcholine,linolenoyl-lysophosphatidylcholine or erucoyl-lysophosphatidylcholine.In another aspect, the liposome or liposome precursor are selected fromat least one or 1-Myristoyl-2-Hydroxy-sn-Glycero-3-Phosphocholine(DMPC), 12-Mysteroyl-2-Hydroxy-sn-Glycero-3-[Phospho-rac-(glycerol)](DMPG), DMPC/DMPG,1-myristoyl-2-hydroxy-sn-glycero-3-phospho-(1′-rac-glycerol) (LysoPG),or 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine (LysoPC). Inanother aspect, the short chain fatty acid is up to 5 carbons, a mediumchain is 6 to 12 carbons, a long chain is 13-21 carbons and a very longchain fatty acid is greater than 22 carbons, including both even and oddchain fatty acids. In another aspect, the short chain fatty acid has 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55 or more carbons,which are saturated or unsaturated. In another aspect, the cardiacchannelopathy or the condition resulting from the irregularity oralteration in the cardiac pattern is inhibition of an ion channelresponsible for the delayed-rectifier K⁺ current in the heart,polymorphic ventricular tachycardia, prolongation of the QTc, LQT2,LQTS, or torsades de pointes. In another aspect, the one or more activeagents is selected from at least one of crizotinib, nilotinib,terfenadine, astemizole, gripafloxacin, terodilene, droperidole,lidoflazine, levomethadyl, sertindoyle or cisapride. In another aspect,the drug is selected from Albuterol (salbutamol), Alfuzosin, Amantadine,Amiodarone, Amisulpride, Amitriptyline, Amoxapine, Amphetamine,Anagrelide, Apomorphine, Arformoterol, Aripiprazole, Arsenic trioxide,Astemizole, Atazanavir, Atomoxetine, Azithromycin, Bedaquiline,Bepridil, Bortezomib, Bosutinib, Chloral hydrate, Chloroquine,Chlorpromazine, Ciprofloxacin, Cisapride, Citalopram, Clarithromycin,Clomipramine, Clozapine, Cocaine, Crizotinib, Dabrafenib, Dasatinib,Desipramine, Dexmedetomidine, Dexmethylphenidate, Dextroamphetamine(d-Amphetamine), Dihydroartemisinin+piperaquine, Diphenhydramine,Disopyramide, Dobutamine, Dofetilide, Dolasetron, Domperidone, Dopamine,Doxepin, Dronedarone, Droperidol, Ephedrine, Epinephrine (Adrenaline),Eribulin, Erythromycin, Escitalopram, Famotidine, Felbamate,Fenfluramine, Fingolimod, Flecainide, Fluconazole, Fluoxetine,Formoterol, Foscarnet, Fosphenytoin, Furosemide (Frusemide),Galantamine, Gatifloxacin, Gemifloxacin, Granisetron, Halofantrine,Haloperidol, Hydrochlorothiazide, Ibutilide, Iloperidone, Imipramine(melipramine), Indapamide, Isoproterenol, Isradipine, Itraconazole,Ivabradine, Ketoconazole, Lapatinib, Levalbuterol (levsalbutamol),Levofloxacin, Levomethadyl, Lisdexamfetamine, Lithium, Mesoridazine,Metaproterenol, Methadone, Methamphetamine (methamfetamine),Methylphenidate, Midodrine, Mifepristone, Mirabegron, Mirtazapine,Moexipril/HCTZ, Moxifloxacin, Nelfinavir, Nicardipine, Nilotinib,Norepinephrine (noradrenaline), Norfloxacin, Nortriptyline, Ofloxacin,Olanzapine, Ondansetron, Oxytocin, Paliperidone, Paroxetine,Pasireotide, Pazopanib, Pentamidine, Perflutren lipid microspheres,Phentermine, Phenylephrine, Phenylpropanolamine, Pimozide, Posaconazole,Probucol, Procainamide, Promethazine, Protriptyline, Pseudoephedrine,Quetiapine, Quinidine, Quinine sulfate, Ranolazine, Rilpivirine,Risperidone, Ritodrine, Ritonavir, Roxithromycin, Salmeterol,Saquinavir, Sertindole, Sertraline, Sevoflurane, Sibutramine,Solifenacin, Sorafenib, Sotalol, Sparfloxacin, Sulpiride, Sunitinib,Tacrolimus, Tamoxifen, Telaprevir, Telavancin, Telithromycin,Terbutaline, Terfenadine, Tetrabenazine, Thioridazine, Tizanidine,Tolterodine, Toremifene, Trazodone, Trimethoprim-Sulfa, Trimipramine,Vandetanib, Vardenafil, Vemurafenib, Venlafaxine, Voriconazole,Vorinostat, or Ziprasidone.

In one embodiment, the present invention includes a method forpreventing or treating one or more adverse reactions arising fromadministration of a therapeutically active agent or a drug in a human oranimal subject comprising the steps of: administering to the human oranimal subject an amount of an amount of a lysophosphatidylglycerol witha basic structure:

wherein R¹ or R² can be any even or odd-chain fatty acid, and R³ can beH, acyl, alkyl, aryl, amino acid, alkenes, alkynes, adapted for oraladministration effective to reduce or prevent the at least one cardiacchannelopathies, I_(Kr) channel inhibition or QT prolongation caused bythe drug; and adapted for oral administration effective to reduce orprevent one or more cardiac channelopathies or conditions resulting fromirregularities or alterations in cardiac patterns caused by the drug;and measuring the effect of the combination of thelysophosphatidylglycerol and the therapeutically active agent or thedrug on the drug-induced channelopathy, wherein the composition reducesor eliminated the channelopathy induced by the therapeutically activeagent or the drug.

In one embodiment, the present invention includes a method forpreventing or treating at least one of I_(Kr) channel inhibition or QTprolongation arising from administration of an active agent that causesa drug-induced channelopathy in a human or animal subject comprising thesteps of: identifying the human or animal subject in need of preventionor treatment of a disease treatable active agent that causes adrug-induced channelopathy; and an amount of a lysophosphatidylglyceroladapted for oral administration effective to reduce or prevent one ormore cardiac channelopathies or conditions resulting from irregularitiesor alterations in cardiac patterns caused by the drug; and administeringto the human or animal subject a therapeutically effective amount of anactive agent that causes a drug-induced channelopathy, wherein the orallysophosphatidylglycerol reduces or eliminates the channelopathy inducedby the therapeutically active agent. In one aspect, the active agent haspreviously failed a clinical trial due to drug-induced IKr channelinhibition or QT prolongation. In another aspect, the method furthercomprises the step of identifying a drug in a clinical trial that failedor has limited clinical use due to drug-induced IKr channel inhibitionor QT prolongation side-effects. In another aspect, the drug is selectedfrom Albuterol (salbutamol), Alfuzosin, Amantadine, Amiodarone,Amisulpride, Amitriptyline, Amoxapine, Amphetamine, Anagrelide,Apomorphine, Arformoterol, Aripiprazole, Arsenic trioxide, Astemizole,Atazanavir, Atomoxetine, Azithromycin, Bedaquiline, Bepridil,Bortezomib, Bosutinib, Chloral hydrate, Chloroquine, Chlorpromazine,Ciprofloxacin, Cisapride, Citalopram, Clarithromycin, Clomipramine,Clozapine, Cocaine, Crizotinib, Dabrafenib, Dasatinib, Desipramine,Dexmedetomidine, Dexmethylphenidate, Dextroamphetamine (d-Amphetamine),Dihydroartemisinin+piperaquine, Diphenhydramine, Disopyramide,Dobutamine, Dofetilide, Dolasetron, Domperidone, Dopamine, Doxepin,Dronedarone, Droperidol, Ephedrine, Epinephrine (Adrenaline), Eribulin,Erythromycin, Escitalopram, Famotidine, Felbamate, Fenfluramine,Fingolimod, Flecainide, Fluconazole, Fluoxetine, Formoterol, Foscarnet,Fosphenytoin, Furosemide (Frusemide), Galantamine, Gatifloxacin,Gemifloxacin, Granisetron, Halofantrine, Haloperidol,Hydrochlorothiazide, Ibutilide, Iloperidone, Imipramine (melipramine),Indapamide, Isoproterenol, Isradipine, Itraconazole, Ivabradine,Ketoconazole, Lapatinib, Levalbuterol (levsalbutamol), Levofloxacin,Levomethadyl, Lisdexamfetamine, Lithium, Mesoridazine, Metaproterenol,Methadone, Methamphetamine (methamfetamine), Methylphenidate, Midodrine,Mifepristone, Mirabegron, Mirtazapine, Moexipril/HCTZ, Moxifloxacin,Nelfinavir, Nicardipine, Nilotinib, Norepinephrine (noradrenaline),Norfloxacin, Nortriptyline, Ofloxacin, Olanzapine, Ondansetron,Oxytocin, Paliperidone, Paroxetine, Pasireotide, Pazopanib, Pentamidine,Perflutren lipid microspheres, Phentermine, Phenylephrine,Phenylpropanolamine, Pimozide, Posaconazole, Probucol, Procainamide,Promethazine, Protriptyline, Pseudoephedrine, Quetiapine, Quinidine,Quinine sulfate, Ranolazine, Rilpivirine, Risperidone, Ritodrine,Ritonavir, Roxithromycin, Salmeterol, Saquinavir, Sertindole,Sertraline, Sevoflurane, Sibutramine, Solifenacin, Sorafenib, Sotalol,Sparfloxacin, Sulpiride, Sunitinib, Tacrolimus, Tamoxifen, Telaprevir,Telavancin, Telithromycin, Terbutaline, Terfenadine, Tetrabenazine,Thioridazine, Tizanidine, Tolterodine, Toremifene, Trazodone,Trimethoprim-Sulfa, Trimipramine, Vandetanib, Vardenafil, Vemurafenib,Venlafaxine, Voriconazole, Vorinostat, or Ziprasidone.

In one embodiment, the present invention includes a method of evaluatinga candidate drug, wherein the candidate drug causes a channelopathy, themethod comprising: (a) administering an amount of an orallysophosphatidylglycerol and a candidate drug to a first subset of thepatients, and a placebo to a second subset of the patients, wherein theoral liposome or liposome precursor is provided in an amount effectiveto reduce or prevent one or more cardiac channelopathies or conditionsresulting from irregularities or alterations in cardiac patterns causedby the candidate drug; (b) measuring the level of channelopathy from thefirst and second set of patients; and (c) determining if the combinationof the oral liposome or liposome precursors and the candidate drugreduce the drug-induced channelopathy that is statistically significantas compared to any reduction occurring in the subset of patients thattook the placebo or to the known drug-induced channelopathy, wherein astatistically significant reduction indicates that the combination ofthe oral lysophosphatidylglycerol and the candidate drug is useful intreating a disease state while also reducing or eliminating thedrug-induced channelopathy. In another aspect, the drug has previouslyfailed a clinical trial due to a drug-induced channelopathy, IKr channelinhibition or QT prolongation. In another aspect, the drug has beenwithdrawn from the marketplace due to a drug-induced channelopathy, IKrchannel inhibition or QT prolongation. In another aspect, the methodfurther comprises the step of repeating steps (a) to (c) after a periodof time. In another aspect, the drug is selected from Albuterol(salbutamol), Alfuzosin, Amantadine, Amiodarone, Amisulpride,Amitriptyline, Amoxapine, Amphetamine, Anagrelide, Apomorphine,Arformoterol, Aripiprazole, Arsenic trioxide, Astemizole, Atazanavir,Atomoxetine, Azithromycin, Bedaquiline, Bepridil, Bortezomib, Bosutinib,Chloral hydrate, Chloroquine, Chlorpromazine, Ciprofloxacin, Cisapride,Citalopram, Clarithromycin, Clomipramine, Clozapine, Cocaine,Crizotinib, Dabrafenib, Dasatinib, Desipramine, Dexmedetomidine,Dexmethylphenidate, Dextroamphetamine (d-Amphetamine),Dihydroartemisinin+piperaquine, Diphenhydramine, Disopyramide,Dobutamine, Dofetilide, Dolasetron, Domperidone, Dopamine, Doxepin,Dronedarone, Droperidol, Ephedrine, Epinephrine (Adrenaline), Eribulin,Erythromycin, Escitalopram, Famotidine, Felbamate, Fenfluramine,Fingolimod, Flecainide, Fluconazole, Fluoxetine, Formoterol, Foscarnet,Fosphenytoin, Furosemide (Frusemide), Galantamine, Gatifloxacin,Gemifloxacin, Granisetron, Halofantrine, Haloperidol,Hydrochlorothiazide, Ibutilide, Iloperidone, Imipramine (melipramine),Indapamide, Isoproterenol, Isradipine, Itraconazole, Ivabradine,Ketoconazole, Lapatinib, Levalbuterol (levsalbutamol), Levofloxacin,Levomethadyl, Lisdexamfetamine, Lithium, Mesoridazine, Metaproterenol,Methadone, Methamphetamine (methamfetamine), Methylphenidate, Midodrine,Mifepristone, Mirabegron, Mirtazapine, Moexipril/HCTZ, Moxifloxacin,Nelfinavir, Nicardipine, Nilotinib, Norepinephrine (noradrenaline),Norfloxacin, Nortriptyline, Ofloxacin, Olanzapine, Ondansetron,Oxytocin, Paliperidone, Paroxetine, Pasireotide, Pazopanib, Pentamidine,Perflutren lipid microspheres, Phentermine, Phenylephrine,Phenylpropanolamine, Pimozide, Posaconazole, Probucol, Procainamide,Promethazine, Protriptyline, Pseudoephedrine, Quetiapine, Quinidine,Quinine sulfate, Ranolazine, Rilpivirine, Risperidone, Ritodrine,Ritonavir, Roxithromycin, Salmeterol, Saquinavir, Sertindole,Sertraline, Sevoflurane, Sibutramine, Solifenacin, Sorafenib, Sotalol,Sparfloxacin, Sulpiride, Sunitinib, Tacrolimus, Tamoxifen, Telaprevir,Telavancin, Telithromycin, Terbutaline, Terfenadine, Tetrabenazine,Thioridazine, Tizanidine, Tolterodine, Toremifene, Trazodone,Trimethoprim-Sulfa, Trimipramine, Vandetanib, Vardenafil, Vemurafenib,Venlafaxine, Voriconazole, Vorinostat, or Ziprasidone.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of the features and advantages of thepresent invention, reference is now made to the detailed description ofthe invention along with the accompanying figures and in which:

FIG. 1 is a graph that shows the effect of DMPC, DMPC+Nilotinib andNilotinib on hERG current density from transfected HEK 293 cells.

FIG. 2 is a graph that shows the effect of DMPG, DMPG+Nilotinib andNilotinib on hERG current density from transfected HEK 293 cells.

FIG. 3 is a graph that shows the effect of DMPC/DMPG,DMPC/DMPG+Nilotinib and Nilotinib on hERG current density fromtransfected HEK 293 cells.

FIG. 4 is a graph that shows the effect of LysoPC, LysoPC+Nilotinib andNilotinib on hERG current density from transfected HEK 293 cells.

FIG. 5 is a graph that shows the effect of LysoPG, LysoPG+Nilotinib andNilotinib on hERG current density from transfected HEK 293 cells.

FIG. 6 is a graph that shows the effect of DMPC, DMPC+Nilotinib,DMPC+Nilotinib (in DMSO) and Nilotinib on hERG current density fromtransfected HEK 293 cells.

FIG. 7 is a graph that shows the effect of DMPG, DMPG+Nilotinib,DMPG+Nilotinib (in DMSO) and Nilotinib on hERG current density fromtransfected HEK 293 cells.

DETAILED DESCRIPTION OF THE INVENTION

While the making and using of various embodiments of the presentinvention are discussed in detail below, it should be appreciated thatthe present invention provides many applicable inventive concepts thatcan be embodied in a wide variety of specific contexts. The specificembodiments discussed herein are merely illustrative of specific ways tomake and use the invention and do not delimit the scope of theinvention.

To facilitate the understanding of this invention, a number of terms aredefined below. Terms defined herein have meanings as commonly understoodby a person of ordinary skill in the areas relevant to the presentinvention. Terms such as “a”, “an” and “the” are not intended to referto only a singular entity, but include the general class of which aspecific example may be used for illustration. The terminology herein isused to describe specific embodiments of the invention, but their usagedoes not delimit the invention, except as outlined in the claims.

Non-limiting exemplary lysophosphatidylglycerols for use with thepresent invention include lysophosphatidylcholines,lauroyl-lysophosphatidylcholine, myristoyl-lysophosphatidylcholine,palmitoyl-lysophosphatidylcholine, stearoyl-lysophosphatidylcholine,arachidoyl-lysophosphatidylcholine, oleoyl-lysophosphatidylcholine,linoleoyl-lysophosphatidylcholine, linolenoyl-lysophosphatidylcholine orerucoyl-lysophosphatidylcholine. Asymmetric phosphatidylcholines arereferred to as 1-acyl, 2-acyl-sn-glycero-3-phosphocholines, wherein theacyl groups are different from each other. Symmetricphosphatidylcholines are referred to as1,2-diacyl-sn-glycero-3-phosphocholines. As used herein, theabbreviation “PC” refers to phosphatidylcholine. The phosphatidylcholine1,2-dimyristoyl-sn-glycero-3-phosphocholine is abbreviated herein as“DMPC.” The phosphatidylcholine 1,2-dioleoyl-sn-glycero-3-phosphocholineis abbreviated herein as “DOPC.” The phosphatidylcholine1,2-dipalmitoyl-sn-glycero-3-phosphocholine is abbreviated herein as“DPPC.” The single fatty acid chain version of these short or long chainfatty acids are referred to as the “lyso” forms when only a single fattyacid chain is attached to the glyceryl backbone.

In one embodiment, the lysophosphatidylglycerol has a basic structure:

wherein R¹ or R² can be any even or odd-chain fatty acid, and R³ can beH, acyl, alkyl, aryl, amino acid, alkenes, alkynes, and wherein a shortchain fatty acid is up to 5 carbons, a medium chain is 6 to 12 carbons,a long chain is 13-21 carbons and a very long chain fatty acid isgreater than 22 carbons, including both even and odd chain fatty acids.In one example, the fatty acids have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,35, 40, 45, 50, 55 or long fatty acids, which can be saturated orunsaturated. The present invention can be used with any QT prolongingdrug, including but not limited to those listed at:www.crediblemeds.org, Albuterol (salbutamol), Alfuzosin, Amantadine,Amiodarone, Amisulpride, Amitriptyline, Amoxapine, Amphetamine,Anagrelide, Apomorphine, Arformoterol, Aripiprazole, Arsenic trioxide,Astemizole, Atazanavir, Atomoxetine, Azithromycin, Bedaquiline,Bepridil, Bortezomib, Bosutinib, Chloral hydrate, Chloroquine,Chlorpromazine, Ciprofloxacin, Cisapride, Citalopram, Clarithromycin,Clomipramine, Clozapine, Cocaine, Crizotinib, Dabrafenib, Dasatinib,Desipramine, Dexmedetomidine, Dexmethylphenidate, Dextroamphetamine(d-Amphetamine), Dihydroartemisinin+piperaquine, Diphenhydramine,Disopyramide, Dobutamine, Dofetilide, Dolasetron, Domperidone, Dopamine,Doxepin, Dronedarone, Droperidol, Ephedrine, Epinephrine (Adrenaline),Eribulin, Erythromycin, Escitalopram, Famotidine, Felbamate,Fenfluramine, Fingolimod, Flecainide, Fluconazole, Fluoxetine,Formoterol, Foscarnet, Fosphenytoin, Furosemide (Frusemide),Galantamine, Gatifloxacin, Gemifloxacin, Granisetron, Halofantrine,Haloperidol, Hydrochlorothiazide, Ibutilide, Iloperidone, Imipramine(melipramine), Indapamide, Isoproterenol, Isradipine, Itraconazole,Ivabradine, Ketoconazole, Lapatinib, Levalbuterol (levsalbutamol),Levofloxacin, Levomethadyl, Lisdexamfetamine, Lithium, Mesoridazine,Metaproterenol, Methadone, Methamphetamine (methamfetamine),Methylphenidate, Midodrine, Mifepristone, Mirabegron, Mirtazapine,Moexipril/HCTZ, Moxifloxacin, Nelfinavir, Nicardipine, Nilotinib,Norepinephrine (noradrenaline), Norfloxacin, Nortriptyline, Ofloxacin,Olanzapine, Ondansetron, Oxytocin, Paliperidone, Paroxetine,Pasireotide, Pazopanib, Pentamidine, Perflutren lipid microspheres,Phentermine, Phenylephrine, Phenylpropanolamine, Pimozide, Posaconazole,Probucol, Procainamide, Promethazine, Protriptyline, Pseudoephedrine,Quetiapine, Quinidine, Quinine sulfate, Ranolazine, Rilpivirine,Risperidone, Ritodrine, Ritonavir, Roxithromycin, Salmeterol,Saquinavir, Sertindole, Sertraline, Sevoflurane, Sibutramine,Solifenacin, Sorafenib, Sotalol, Sparfloxacin, Sulpiride, Sunitinib,Tacrolimus, Tamoxifen, Telaprevir, Telavancin, Telithromycin,Terbutaline, Terfenadine, Tetrabenazine, Thioridazine, Tizanidine,Tolterodine, Toremifene, Trazodone, Trimethoprim-Sulfa, Trimipramine,Vandetanib, Vardenafil, Vemurafenib, Venlafaxine, Voriconazole,Vorinostat, or Ziprasidone.

Human ether-a-go-go-related gene (hERG) Potassium channel anti-blockadeby liposome and fragments.

Potassium channels conduct the rapid component of the delayed rectifierpotassium current, Kir, which is crucial for repolarization of cardiacaction potentials. A reduction in hERG currents due to either geneticdefects or adverse drug effects can lead to hereditary or acquired longQT syndromes characterized by action potential prolongation, lengtheningof the QT interval on the surface ECG, and an increased risk for“torsade de pointes” arrhythmias and sudden death. This undesirable sideeffect of non-antiarrhythmic compounds has prompted the withdrawal ofdrugs from the market. Studies on mechanisms of hERG channel inhibitionprovide significant insights into the molecular factors that determinestate-, voltage-, and use-dependency of hERG current block. Mutationsaltering properties of the high-affinity drug binding site in hERG andits interaction with drug molecules cause current increase andhereditary short QT syndrome with a high risk for life-threateningarrhythmias. (Thomas D1, 2006).

Anatomical Characteristics of the K+ Channel.

The types and distributions of inwardly rectifying potassium (Kir)channels are one of the major determinants of the electrophysiologicalproperties of cardiac myocytes. Inward rectifier potassium (Kir)channels regulate cell excitability and transport of K+ ions across cellmembranes.

The potassium channel from Streptomyces lividans is an integral membraneprotein with sequence similarity to all known K⁺ channels, particularlyin the pore region. X-ray analysis with data to 3.2 angstroms revealsthat four identical subunits create an inverted teepee, or cone,cradling the selectivity filter of the pore in its outer end. The narrowselectivity filter is only 12 angstroms long, whereas the remainder ofthe pore is wider and lined with hydrophobic amino acids. A largewater-filled cavity and helix dipoles are positioned so as to overcomeelectrostatic destabilization of an ion in the pore at the center of thebilayer. Main chain carbonyl oxygen atoms from the K⁺ channel signaturesequence line the selectivity filter, which is held open by structuralconstraints to coordinate K⁺ ions but not smaller Na⁺ ions. Theselectivity filter contains two K⁺ ions about 7.5 angstroms apart. Ionchannels exhibit ion selectivity through pore architecture that conductsspecific ions. This configuration promotes ion conduction by exploitingelectrostatic repulsive forces to overcome attractive forces between K⁺ions and the selectivity filter. The architecture of the poreestablishes the physical principles underlying selective K⁺ conduction.(Doyle D A, 1998).

Another member of the inward-rectifier family of potassium channels isthe prokaryotic KirBac1.1 channel. The structure of the Kir channelassembly in the closed state, when refined to a resolution of 3.65angstroms contains a main activation gate and structural elementsinvolved in gating. On the basis of structural evidence, gating involvescoupling between the intracellular and membrane domains suggesting thatinitiation of gating by membrane or intracellular signals representsdifferent entry points to a common mechanistic pathway. (Kuo, A 2003).

Kir channels in the cardiac myocytes may be actively regulated by meansof the change in PIP(2) level rather than by downstream signaltransduction pathways. The classical inward rectifier K(+) channel),Kir2.1, Kir6.2/SUR2A (ATP-sensitive K(+) channel) and Kir3.1/3.4(muscarinic K(+) channels) in cardiac myocytes are commonly upregulatedby a membrane lipid, phosphatidylinositol 4,5-bisphosphates (PIP(2)).PIP(2) interaction sites appear to be conserved by positively chargedamino acid residues and the putative alpha-helix in the C-terminals ofKir channels. PIP(2) level in the plasma membrane is regulated bytagonist stimulation (Takano M I 2003).

Inward rectifier potassium channels are characterized by twotransmembrane helices per subunit, plus an intracellular C-terminaldomain that controls channel gating in response to changes inconcentration of various ligands. Based on the crystal structure of thetetrameric C-terminal domain of Kir3.1, it is possible to build ahomology model of the ATP-binding C-terminal domain of Kir6.2. Moleculardynamics simulations are used to probe the dynamics of Kir C-terminaldomains and to explore the relationship between their dynamics andpossible mechanisms of channel gating. Multiple simulations, each of 10ns duration, were performed for Kir3.1 (crystal structure) and Kir6.2(homology model), in both their monomeric and tetrameric forms. TheKir6.2 simulations were performed with and without bound ATP. Theresults of the simulations reveal comparable conformational stabilityfor the crystal structure and the homology model. There is decrease inconformational flexibility when comparing the monomers with thetetramers, corresponding mainly to the subunit interfaces in thetetramer. The beta-phosphate of ATP interacts with the side chain ofK185 in the Kir6.2 model and simulations. The flexibility of the Kir6.2tetramer is not changed greatly by the presence of bound ATP, other thanin two loop regions. Principal components analysis of the simulateddynamics suggests loss of symmetry in both the Kir3.1 and Kir6.2tetramers, consistent with “dimer-of-dimers” motion of subunits inC-terminal domains of the corresponding Kir channels. This is suggestiveof a gating model in which a transition between exact tetramericsymmetry and dimer-of-dimers symmetry is associated with a change intransmembrane helix packing coupled to gating of the channel.Dimer-of-dimers motion of the C-terminal domain tetramer is alsosupported by coarse-grained (anisotropic network model) calculations.Loss of exact rotational symmetry is suggested to play a role in gatingin the bacterial Kir homolog, KirBac1.1, and in the nicotinicacetylcholine receptor channel. (Haider S I, 2005).

Homotetrameric models of three mammalian Kir channels (Kir1.1, Kir3.1,and Kir6.2) have been generated, using the KirBac3.1 transmembrane andrat Kir3.1 intracellular domain structures as templates. All threemodels were explored by 10 ns molecular dynamics simulations inphospholipid bilayers. Analysis of the initial structures revealedconservation of potential lipid interaction residues (Trp/Tyr andArg/Lys side chains near the lipid headgroup-water interfaces).Examination of the intracellular domains revealed key structuraldifferences between Kir1.1 and Kir6.2 which may explain the differencein channel inhibition by ATP. The behavior of all three models in the MDsimulations revealed that they have conformational stability similar tothat seen for comparable simulations of, for example, structures derivedfrom cryoelectron microscopy data. Local distortions of the selectivityfilter were seen during the simulations, as observed in previoussimulations of KirBac and in simulations and structures of KcsA. Thesemay be related to filter gating of the channel. The intracellularhydrophobic gate does not undergo any substantial changes during thesimulations and thus remains functionally closed. Analysis oflipid-protein interactions of the Kir models emphasizes the key role ofthe M0 (or “slide”) helix which lies approximately parallel to thebilayer-water interface and forms a link between the transmembrane andintracellular domains of the channel (Haider S I, 2007).

The potassium-selective transmembrane pore in voltage-activated K+channels is gated by changes in the membrane potential. Activationgating (opening) occurs in milliseconds and involves a gate at thecytoplasmic side of the pore. Substituting cysteine at a particularposition in the last transmembrane region (S6) of the homotetramericShaker K+ channel creates metal binding sites at which Cd2+ ions canbind with high affinity. The bound Cd2+ ions form a bridge between theintroduced cysteine in one channel subunit and a native histidine inanother subunit, and the bridge traps the gate in the open state. Theseresults suggest that gating involves a rearrangement of the intersubunitcontacts at the intracellular end of S6. The structure of a bacterial K+channel shows that the S6 homologs cross in a bundle, leaving anaperture at the bundle crossing. In the context of this structure, themetal ions form a bridge between a cysteine above the bundle crossingand a histidine below the bundle crossing in a neighboring subunit.results suggest that gating occurs at the bundle crossing, possiblythrough a change in the conformation of the bundle itself (Holmgren M L2002).

Activated gating in voltage-activated K+ channels are apotassium-selective transmembrane pore gated by changes in the membranepotential. This activation gating (opening) occurs in milliseconds andinvolves a gate at the cytoplasmic side of the pore. Substitutingcysteine at a particular position in the last transmembrane region (S6)of the homotetrameric Shaker K+ channel creates metal binding sites atwhich Cd2+ ions can bind with high affinity. The bound Cd2+ ions form abridge between the introduced cysteine in one channel subunit and anative histidine in another subunit, and the bridge traps the gate inthe open state. These results suggest that gating involves arearrangement of the intersubunit contacts at the intracellular end ofS6. The structure of a bacterial K+ channel shows that the S6 homologscross in a bundle, leaving an aperture at the bundle crossing. In thecontext of this structure, the metal ions form a bridge between acysteine above the bundle crossing and a histidine below the bundlecrossing in a neighboring subunit. results suggest that gating occurs atthe bundle crossing, possibly through a change in the conformation ofthe bundle itself (Holmgren M L 2002).

Channelopathies

The human ether-à-go-go gene related cardiac tetrameric potassiumchannel. when mutated can render patients sensitive to over 163 drugswhich may inhibit ion conduction and deregulate action potentials.(Credible Meds) Prolongation of the action potential follows effects inthe potassium channel. Ion channel active drugs may directly increasethe QTc interval, and increase the risk of torsade de point and suddencardiac death. (Table 1) Exacerbation of cardiomyocyte potassium channelsensitivity to drugs may also be associated with metabolic diseasedstates including diabetes(Veglio M, 2002) or may be of idiopathicorigin.

For these reasons, evaluation of drug effects on cardiomyocyte potassiumchannel function is a critical step during drug development, and whenserious, may be an obstacle to regulatory approval. In whole-cellpatch-clamp experiments, curcumin inhibited hERG K⁺ currents in HEK293cells stably expressing hERG channels in a dose-dependent manner, withIC₅₀ value of 5.55 μM. The deactivation, inactivation and the recoverytime from inactivation of hERG channels were significantly changed byacute treatment of 10 μM curcumin. Incubation of 20 μM curcumin for 24 hreduced the HEK293 cell viability. Intravenous injection of 20 mg ofcurcumin in rabbits did not affect the cardiac repolarization manifestedby QTc values. (Hu C W 2012). However, SignPath Pharma has discoveredspecific molecules which antagonize QTc prolonging drugs (Helson L, 2002Ranjan A, 2014, Shopp G, 2014). These molecules are specific liposomes,or components of liposomes which were initially bound to lipophilicdrugs to permit intravenous solubility at physiological conditions, andreduce adverse events. The loci of action appears to be in intra-channelion selectivity or gating site(s) controlling potassium ion movement: akey functional component of regulation of action potentials which leaddownstream to myocyte contraction.

The mechanism of human ether-à-go-go related gene channels blocade maybe analogous to the effects of externally applied quaternary ammoniumderivatives which indirectly may suggest the mechanism of action of theanti-blockading effect of the DMPC/DMPG liposome or its metabolites. Theinhibitory constants and the relative binding energies for channelinhibition indicate that more hydrophobic quaternary ammoniums havehigher affinity blockade while cation-π interactions or size effects arenot a deterministic factor in channel inhibition by quaternaryammoniums. Also hydrophobic quaternary ammoniums either with a longertail group or with a bigger head group than tetraethylammonium permeatethe cell membrane to easily access the high-affinity internal bindingsite in the gene channel and exert a stronger blockade.

Although these data suggest that the basis for the ameliorating effectliposome, or its components is the higher competitive affinity forbinding sites by the, DMPC and DMPG compared to QTc prolonging drugs( ),its constitutive lack of ion transport modulation, i.e. liposome or itsfragments do not impede K+ ion transport indicates that

By way of explanation, and in no way a limitation of these claims, thesedata suggest that the basis for the ameliorating effect liposome, or itscomponents, is the higher competitive affinity for binding sites by theDMPC and DMPG compared to QTc prolonging drugs, its constitutive lack ofion transport modulation, i.e., liposome, or its fragments, do notimpede K+ ion transport and indicates that the site of the mechanism ofDMPC or DMPG protection may be in the selectivity segment of the channelor in the hydration surrounding the ion.

Additionally, based upon these hERG channel data the structures of theseliposome components may be informative for designing or selecting othermolecules to prevent drug induced cardiac arrhythmias.

This study provides additional information as to the QTc modulatingeffects by drugs, induced in cardiac myocyte potassium channels, andmitigation by liposomes and liposomal constituents. The latter moleculespresent an opportunity to probe the K⁺ channels as targets forpharmacological mitigation of drug-induced channelopathies.

Evaluation of the protective effect of DMPC, DMPG, DMPC/DMPG, LysoPG andLysoPC against hERG inhibition by Nilotinib.

Purpose of the study: The purpose of this study is to evaluate in vitrothe protective effect of DMPC, DMPG, DMPC/DMPG, LysoPG and LysoPC on therapidly activating delayed-rectifier potassium selective current(I_(Kr)) generated under normoxic conditions in stably transfected HumanEmbryonic Kidney cells (HEK 293 cells). This study was designed as ascreen and does not require QA involvement (non-GLP-compliant).

Test Articles:

1—DMPC

2—DMPG

3—DMPC/DMPG 90:9

4—14:0 LysoPC

5—14:0 LysoPG

6—DMPC+Nilotinib (0.1 μM)

7—DMPG+Nilotinib (0.1 μM)

8—DMPC/DMPG 90:9+Nilotinib (0.1 μM)

9—14:0 LysoPC+Nilotinib (0.1 μM)

10—14:0 LysoPG+Nilotinib (0.1 μM)

Test System: hERG-expressing HEK 293 transfected cell line. Testperformed: Whole-cell patch-clamp current acquisition and analysis.Experimental Temperature: 35±2° C.

Application of Test Articles:

5 minutes of exposure to each concentration in presence of closedcircuit perfusion (2 mL/min). 5 minutes for washout periods in presenceof a flow-through perfusion (2 mL/min) in addition to a closed circuitperfusion (2 mL/min). The positive control (Nilotinib, 0.05 μg/mL) wasadded to naive cells obtained from the same cell line and same passagefor a period of 5 minutes in presence of a closed circuit perfusion (2mL/min).

Cells were under continuous stimulation of the pulses protocolthroughout the experiments and cell currents were recorded after 5minutes of exposure to each condition.

Original data acquisition design: Acquisition Rate(s): 1.0 kHz.

Design for acquisition when testing the compound or the vehicle/solventequivalent:

-   -   1 recording made in baseline condition    -   1 recording made in the presence of concentration 1

Design for acquisition when testing the positive control:

-   -   1 recording made in baseline condition    -   1 recording made in the presence of the positive control    -   n=number of responsive cells patched on which the whole protocol        above could be applied.

Statistical analysis: Statistical comparisons were made using pairedStudent's t-tests. The currents recorded obtained on day 2, 3 and 4 werestatistically compared to the currents recorded on day 1.

The currents recorded after the positive control (nilotinib alone)exposure were compared to the currents recorded in baseline conditions.

Differences were considered significant when p≤0.05.

Exclusion Criteria:

-   -   1. Timeframe of drug exposure not respected    -   2. Instability of the seal    -   3. No tail current generated by the patched cell    -   4. No significant effect of the positive control    -   5. More than 10% variability in capacitance transient amplitude        over the duration of the Study.

Effect of the Test Articles on whole-cell I_(Kr) hERG currents.Whole-cell currents elicited during a voltage pulse were recorded inbaseline conditions and following the application of the selectedconcentration of test article. The cells were depolarized for one secondfrom the holding potential (−80 mV) to a maximum value of +40 mV,starting at −40 mV and progressing in 10 mV increments. The membranepotential was then repolarized to −55 mV for one second, and finallyreturned to −80 mV.

Whole-cell tail current amplitude was measured at a holding potential of−55 mV, following activation of the current from −40 to +40 mV. Currentamplitude was measured at the maximum (peak) of this tail current.Current density was obtained by dividing current amplitude by cellcapacitance measured prior to capacitive transient minimization.

Current run-down and solvent effect correction. All data pointspresented in this Study Report have been corrected for solvent effectand time-dependent current run-down. Current run-down and solventeffects were measured simultaneously by applying the experimental designin test-article free conditions over the same time frame as was donewith the test article. The loss in current amplitude measured duringthese so-called vehicle experiments (representing both solvent effectsand time-dependent run-down) was subtracted from the loss of amplitudemeasured in the presence of the test article to isolate the effect ofthe test article, apart from the effect of the solvent and theinevitable run-down in current amplitude over time.

TABLE 1 Effect of DMPC, DMPC + Nilotinib and Nilotinib on hERG currentdensity from transfected HEK 293 cells. Normalized Corrected CurrentNormalized p Density Current Density SEM value n = Baseline 1.000 1.000n/a n/a 3 DMPC 0.863 1.056 0.056 0.423 3 Nilotinib, 0.1 μM 0.308 0.459*0.070 0.016 3 DMPC + Nilotinib, 0.836 1.029 0.023 0.328 3 0.1 μM

FIG. 1 is a graph that shows the effect of DMPC, DMPC+Nilotinib andNilotinib on hERG current density from transfected HEK 293 cells.

TABLE 2 Effect of DMPG, DMPG + Nilotinib and Nilotinib on hERG currentdensity from transfected HEK 293 cells. Normalized Corrected CurrentNormalized p Density Current Density SEM value n = Baseline 1.000 1.000n/a n/a 3 DMPG 0.800 0.994 0.044 0.901 3 Nilotinib, 0.1 μM 0.308 0.459*0.070 0.016 3 DMPG + Nilotinib, 0.743 0.936 0.067 0.437 3 0.1 μM

FIG. 2 is a graph that shows the effect of DMPG, DMPG+Nilotinib andNilotinib on hERG current density from transfected HEK 293 cells.

TABLE 3 Effect of DMPC/DMPG, DMPC/DMPG + Nilotinib and Nilotinib on hERGcurrent density from transfected HEK 293 cells. Normalized CorrectedCurrent Normalized Density Current Density SEM p value n = Baseline1.000 1.000 n/a n/a 3 DMPC-DMPG 0.871 1.064 0.127 0.647 4 Nilotinib, 0.1μM 0.308 0.459* 0.070 0.016 3 DMPC/DMPG + 0.773 0.966 0.098 0.754 4Nilotinib, 0.1 μM

FIG. 3 is a graph that shows the effect of DMPC/DMPG,DMPC/DMPG+Nilotinib and Nilotinib on hERG current density fromtransfected HEK 293 cells.

TABLE 4 Effect of LysoPC, LysoPC + Nilotinib and Nilotinib on hERGcurrent density from transfected HEK 293 cells. Normalized CorrectedCurrent Normalized p Density Current Density SEM value n = Baseline1.000 1.000 n/a n/a 3 LysoPC 0.647 0.840* 0.040 0.028 4 Nilotinib, 0.1μM 0.308 0.459* 0.070 0.016 3 LysoPC + 0.865 1.097 0.055 0.553 3Nilotinib, 0.1 μM

FIG. 4 is a graph that shows the effect of LysoPC, LysoPC+Nilotinib andNilotinib on hERG current density from transfected HEK 293 cells.

TABLE 5 Effect of LysoPG, LysoPG + Nilotinib and Nilotinib on hERGcurrent density from transfected HEK 293 cells. Normalized CorrectedCurrent Normalized p Density Current Density SEM value n = Baseline1.000 1.000 n/a n/a 3 14:0 LysoPG, 0.930 1.124 0.128 0.435 3 0.45 μg/mLNilotinib, 0.1 μM 0.308 0.459* 0.070 0.016 3 14:0 LysoPG + 0.743 0.9360.067 0.437 3 Nilotinib, 0.1 μM

FIG. 5 is a graph that shows the effect of LysoPG, LysoPG+Nilotinib andNilotinib on hERG current density from transfected HEK 293 cells.

This study aimed at quantifying the protective effect of DMPC, DMPG,DMPC/DMPG, LysoPG and LysoPC against the inhibition of the rapidlyactivating delayed-rectifier potassium selective current (I_(Kr))generated under normoxic conditions in stably transfected HumanEmbryonic Kidney (HEK) 293 cells caused by the Nilotinib.

All data points presented in this study have been corrected for solventeffects and time-dependent current run-down. These two parameters wereevaluated by applying exactly the same experimental design to thevehicle as that done with the test articles. The currents were measuredover the same time course as was done in the presence of the testarticle. The values obtained, representing both solvent effects andtime-dependent run-down, were used to correct the effect of the testarticles, if any. This ensures that changes attributable to time or thesolvent are not mistakenly attributed to the test articles.

DMPC, DMPG, DMPC/DMPG and LysoPG alone did not cause any inhibition ofthe hERG tail current density (n=3). LysoPC alone caused 16% ofinhibition of the hERG tail current density (n=4).

Nilotinib alone, formulated in DMSO at 0.1 μM, caused 54.1% ofinhibition of the hERG tail current (n=3). The inhibition observed is inline with previous data generated in identical conditions, and agreeswith reported inhibition values for this compound.

Nilotinib when formulated in an aqueous solution containing DMPC, DMPG,DMPC/DMPC, LysoPG or LysoPC (ratio 1:9) did not cause any inhibition ofthe hERG tail current.

These data suggest that co-formulating Nilotinib with DMPC, DMPG,DMPC/DMPC, LysoPG and LysoPC protects against hERG inhibition caused byNilotinib.

In this study, the DMPC+Nilotinib, DMPG+Nilotinib, DMPC/DMPC+Nilotinib,LysoPG+Nilotinib or LysoPC+Nilotinib were all formulated using the samemethod. The appropriate amount of Nilotinib powder was dissolved in anaqueous solution containing either DMPC, DMPG, DMPC/DMPC, LysoPG orLysoPC (ratio 9:1). The solution was vortexed for 10 minutes beforebeing used in the patch-clamp assay.

In contrast, the Nilotinib used for the cells exposed to Nilotinib alonewas dissolved in DMSO. Additional studies were conducted to determinewhether the difference in hERG inhibition between DMSO-formulatedNilotinib and lipid-co-formulated Nilotinib resulted from the differentformulations (aqueous or DMSO-based).

Steps for the Study:

Step 1 Step 2 Step 3 Step 4 Baseline TA* added into the 5 minutesexposure TA recording recording experimental chamber time *TA = 1- DMPC(in aqueous solution) 2- DMPG (in aqueous solution) 3- DMPC/DMPG 90:9(in aqueous solution) 4- 14:0 LysoPC (in aqueous solution) 5- 14:0LysoPG (in aqueous solution) 6- DMPC + Nilotinib (0.1 μM) (in aqueoussolution) 7- DMPG + Nilotinib (0.1 μM) (in aqueous solution) 8-DMPC/DMPG 90:9 + Nilotinib (0.1 μM) (in aqueous solution) 9- 14:0LysoPC + Nilotinib (0.1 μM) (in aqueous solution) 10- 14:0 LysoPG +Nilotinib (0.1 μM) (in aqueous solution) 11- Nilotinib alone (in DMSO)

Amongst the mechanisms considered to explain the protection of hERGcurrents were the possibility that DMPC/DMPG or the Lyso-variantsquenched the Nilotinib at the moment of formulation, essentiallypreventing it from getting into the channel at its receptor site.Another possibility was that Nilotinib was less soluble in an aqueoussolution, and therefore was incompletely solubilized at 0.1 μM.

To test both hypotheses, Nilotinib was formulated in DMSO and added intothe experimental chamber following the addition of the DMPC or DMPG.This was based on the principle that 1—adding DMPC/DMPG alone, followedby DMSO-formulated Nilotinib, would eliminate the possibility of earlyquenching of Nilotinib by the lysosome; and 2—that DMSO would maintainthe solubility of Nilotinib (the “Nilotinib-only” inhibition of hERG wasobserved when DMSO-formulated Nilotinib was added to the cells).

Steps for the Following Data

Step 1 Step 2 Step 3 Step 4 Step 5 Step 6 Base- DMPC or 5 minutes DMPCor Nilotinib in DMPC or line DMPG exposure DMPG DMSO DMPG + record-added time recording added Nilotinib ing into the into the (inexperimental experimental DMSO) chamber chamber recording

TABLE 6 Effect of DMPC, DMPC + Nilotinib, DMPC + Nilotinib (in DMSO) andNilotinib on hERG current density from transfected HEK 293 cells.Corrected Normalized Normalized Current Current p Density Density SEMvalue n = Baseline 1.000 1.000 n/a n/a 3 DMPC 0.863 1.056 0.056 0.423 3Nilotinib, 0.1 μM 0.308 0.459* 0.070 0.016 3 DMPC + Nilotinib, 0.8361.029 0.023 0.328 3 0.1 μM (Aqueous) DMPC + Nilotinib 0.164 0.358* 0.0200.019 2 (in DMSO), 0.1 μM

FIG. 6 is a graph that shows the effect of DMPC, DMPC+Nilotinib,DMPC+Nilotinib (in DMSO) and Nilotinib on hERG current density fromtransfected HEK 293 cells.

TABLE 7 Effect of DMPG, DMPG + Nilotinib, DMPG + Nilotinib (in DMSO) andNilotinib on hERG current density from transfected HEK 293 cells.Normalized Corrected Current Normalized p Density Current Density SEMvalue n = Baseline 1.000 1.000 n/a n/a 3 DMPG 0.800 0.994 0.044 0.901 3Nilotinib, 0.1 μM 0.308 0.459* 0.070 0.016 3 DMPG + Nilotinib, 0.7430.936 0.067 0.437 3 0.1 μM DMPG + Nilotinib 0.630 0.823 0.290 0.651 2(in DMSO), 0.1 μM

FIG. 7 is a graph that shows the effect of DMPG, DMPG+Nilotinib,DMPG+Nilotinib (in DMSO) and Nilotinib on hERG current density fromtransfected HEK 293 cells.

It is contemplated that any embodiment discussed in this specificationcan be implemented with respect to any method, kit, reagent, orcomposition of the invention, and vice versa. Furthermore, compositionsof the invention can be used to achieve methods of the invention.

It will be understood that particular embodiments described herein areshown by way of illustration and not as limitations of the invention.The principal features of this invention can be employed in variousembodiments without departing from the scope of the invention. Thoseskilled in the art will recognize, or be able to ascertain using no morethan routine experimentation, numerous equivalents to the specificprocedures described herein. Such equivalents are considered to bewithin the scope of this invention and are covered by the claims.

All publications and patent applications mentioned in the specificationare indicative of the level of skill of those skilled in the art towhich this invention pertains. All publications and patent applicationsare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

The use of the word “a” or “an” when used in conjunction with the term“comprising” in the claims and/or the specification may mean “one,” butit is also consistent with the meaning of “one or more,” “at least one,”and “one or more than one.” The use of the term “or” in the claims isused to mean “and/or” unless explicitly indicated to refer toalternatives only or the alternatives are mutually exclusive, althoughthe disclosure supports a definition that refers to only alternativesand “and/or.” Throughout this application, the term “about” is used toindicate that a value includes the inherent variation of error for thedevice, the method being employed to determine the value, or thevariation that exists among the study subjects.

As used in this specification and claim(s), the words “comprising” (andany form of comprising, such as “comprise” and “comprises”), “having”(and any form of having, such as “have” and “has”), “including” (and anyform of including, such as “includes” and “include”) or “containing”(and any form of containing, such as “contains” and “contain”) areinclusive or open-ended and do not exclude additional, unrecitedelements or method steps. In embodiments of any of the compositions andmethods provided herein, “comprising” may be replaced with “consistingessentially of” or “consisting of”. As used herein, the phrase“consisting essentially of” requires the specified integer(s) or stepsas well as those that do not materially affect the character or functionof the claimed invention. As used herein, the term “consisting” is usedto indicate the presence of the recited integer (e.g., a feature, anelement, a characteristic, a property, a method/process step or alimitation) or group of integers (e.g., feature(s), element(s),characteristic(s), propertie(s), method/process steps or limitation(s))only.

The term “or combinations thereof” as used herein refers to allpermutations and combinations of the listed items preceding the term.For example, “A, B, C, or combinations thereof” is intended to includeat least one of: A, B, C, AB, AC, BC, or ABC, and if order is importantin a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB.Continuing with this example, expressly included are combinations thatcontain repeats of one or more item or term, such as BB, AAA, AB, BBC,AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan willunderstand that typically there is no limit on the number of items orterms in any combination, unless otherwise apparent from the context.

As used herein, words of approximation such as, without limitation,“about”, “substantial” or “substantially” refers to a condition thatwhen so modified is understood to not necessarily be absolute or perfectbut would be considered close enough to those of ordinary skill in theart to warrant designating the condition as being present. The extent towhich the description may vary will depend on how great a change can beinstituted and still have one of ordinary skilled in the art recognizethe modified feature as still having the required characteristics andcapabilities of the unmodified feature. In general, but subject to thepreceding discussion, a numerical value herein that is modified by aword of approximation such as “about” may vary from the stated value byat least ±1, 2, 3, 4, 5, 6, 7, 10, 12 or 15%.

All of the compositions and/or methods disclosed and claimed herein canbe made and executed without undue experimentation in light of thepresent disclosure. While the compositions and methods of this inventionhave been described in terms of preferred embodiments, it will beapparent to those of skill in the art that variations may be applied tothe compositions and/or methods and in the steps or in the sequence ofsteps of the method described herein without departing from the concept,spirit and scope of the invention. All such similar substitutes andmodifications apparent to those skilled in the art are deemed to bewithin the spirit, scope and concept of the invention as defined by theappended claims.

REFERENCES

U.S. Patent Publication No. 2010/0004549: System and Method of SerialComparison for Detection of Long QT Syndrome (LQTS).

U.S. Patent Publication No. 2008/0255464: System and Method forDiagnosing and Treating Long QT Syndrome.

U.S. Patent Publication No. 2007/0048284: Cardiac Arrhythmia TreatmentMethods.

U.S. Patent Publication No. 2001/00120890: Ion Channel ModulatingActivity I.

What is claimed is:
 1. A composition for preventing one or more cardiacchannelopathies, irregularities, or alterations in cardiac patternscaused by an active agent or a drug in a human or animal subjectconsisting of: a therapeutically effective amount of the active agent orthe drug, wherein the active agent or drug causes one or more cardiacchannelopathies, irregularities, or alterations in cardiac patterns; andan amount of a lysophosphatidylglycerol in the form of empty liposomesadapted for oral administration effective to reduce or prevent one ormore cardiac channelopathies or conditions resulting from irregularitiesor alterations in cardiac patterns caused by the active agent or drug,wherein the lysophosphatidylglycerol includes at least one of alysophosphatidylcholine, lauroyl-lysophosphatidylcholine,myristoyl-lysophosphatidylcholine, palmitoyl-lysophosphatidylcholine,stearoyl-lysophosphatidylcholine, arachidoyl-lysophosphatidylcholine,oleoyl-lysophosphatidylcholine, linoleoyl-lysophosphatidylcholine,linolenoyl-lysophosphatidylcholine or erucoyl-lysophosphatidylcholine.2. The composition of claim 1, wherein the lysophosphatidylglycerolinclude at least one or 1-Myristoyl-2-Hydroxy-snGlycero-3-Phosphocholine(DMPC), 1,2-Dimyristoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DMPG),DMPC/DMPG, 1-myristoyl-2-hydroxy-sn-glycero-3-phospho-(1′-rac-glycerol)(LysoPG), or 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine (LysoPC).3. The composition of claim 1, wherein the lysophosphatidylglycerol isdefined further as a short chain fatty acid is up to 5 carbons, a mediumchain is 6 to 12 carbons, a long chain is 13-21 carbons and a very longchain fatty acid is greater than 22 carbons, including both even and oddchain fatty acids.
 4. The composition of claim 1, wherein thelysophosphatidylglycerol has 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40,45, 50, 55 or more carbons, which are saturated or unsaturated.
 5. Thecomposition of claim 1, wherein the cardiac channelopathy or thecondition resulting from the irregularity or alteration in the cardiacpattern is inhibition of an ion channel responsible for thedelayed-rectifier K+ current in the heart, polymorphic ventriculartachycardia, prolongation of the QTc, LQT2, LQTS, or torsades depointes.
 6. The composition of claim 1, wherein the composition is usedfor the treatment or prevention of prolongation of the IKr channelinhibition or QT prolongation induced by administration of the activeagent or drug used in the treatment of cardiac, allergic, or cancerrelated diseases.
 7. The composition of claim 1, wherein the activeagent drug is selected from at least one of crizotinib, nilotinib,terfenadine, astemizole, gripafloxacin, terodilene, droperidole,lidoflazine, levomethadyl, sertindoyle or cisapride.
 8. The compositionof claim 1, wherein the active agent drug is provided enterally,parenterally, intravenously, intraperitoneally, or orally.
 9. Thecomposition of claim 1, wherein the drug is selected from Albuterol(salbutamol), Alfuzosin, Amantadine, Amiodarone, Amisulpride,Amitriptyline, Amoxapine, Amphetamine, Anagrelide, Apomorphine,Arformoterol, Aripiprazole, Arsenic trioxide, Astemizole, Atazanavir,Atomoxetine, Azithromycin, Bedaquiline, Bepridil, Bortezomib, Bosutinib,Chloral hydrate, Chloroquine, Chlorpromazine, Ciprofloxacin, Cisapride,Citalopram, Clarithromycin, Clomipramine, Clozapine, Cocaine,Crizotinib, Dabrafenib, Dasatinib, Desipramine, Dexmedetomidine,Dexmethylphenidate, Dextroamphetamine (d-Amphetamine),Dihydroartemisinin+piperaquine, Diphenhydramine, Disopyramide,Dobutamine, Dofetilide, Dolasetron, Domperidone, Dopamine, Doxepin,Dronedarone, Droperidol, Ephedrine, Epinephrine (Adrenaline), Eribulin,Erythromycin, Escitalopram, Famotidine, Felbamate, Fenfluramine,Fingolimod, Flecainide, Fluconazole, Fluoxetine, Formoterol, Foscarnet,Fosphenytoin, Furosemide (Frusemide), Galantamine, Gatifloxacin,Gemifloxacin, Granisetron, Halofantrine, Haloperidol,Hydrochlorothiazide, Ibutilide, Iloperidone, Imipramine (melipramine),Indapamide, Isoproterenol, Isradipine, Itraconazole, Ivabradine,Ketoconazole, Lapatinib, Levalbuterol (levsalbutamol), Levofloxacin,Levomethadyl, Lisdexamfetamine, Lithium, Mesoridazine, Metaproterenol,Methadone, Methamphetamine (methamfetamine), Methylphenidate, Midodrine,Mifepristone, Mirabegron, Mirtazapine, Moexipril/HCTZ, Moxifloxacin,Nelfinavir, Nicardipine, Nilotinib, Norepinephrine (noradrenaline),Norfloxacin, Nortriptyline, Ofloxacin, Olanzapine, Ondansetron,Oxytocin, Paliperidone, Paroxetine, Pasireotide, Pazopanib, Pentamidine,Perflutren lipid microspheres, Phentermine, Phenylephrine,Phenylpropanolamine, Pimozide, Posaconazole, Probucol, Procainamide,Promethazine, Protriptyline, Pseudoephedrine, Quetiapine, Quinidine,Quinine sulfate, Ranolazine, Rilpivirine, Risperidone, Ritodrine,Ritonavir, Roxithromycin, Salmeterol, Saquinavir, Sertindole,Sertraline, Sevoflurane, Sibutramine, Solifenacin, Sorafenib, Sotalol,Sparfloxacin, Sulpiride, Sunitinib, Tacrolimus, Tamoxifen, Telaprevir,Telavancin, Telithromycin, Terbutaline, Terfenadine, Tetrabenazine,Thioridazine, Tizanidine, Tolterodine, Toremifene, Trazodone,Trimethoprim-Sulfa, Trimipramine, Vandetanib, Vardenafil, Vemurafenib,Venlafaxine, Voriconazole, Vorinostat, or Ziprasidone.
 10. A compositionfor preventing or treating a diseases with an active agent or drug thatcauses one or more adverse reactions arising from administration of anactive agent or drug in a human that causes at least one of cardiacchannelopathies, IKr channel inhibition or QT prolongation consistingof: a therapeutically effective amount of the active agent or the drug,wherein the active agent or drug causes the at least one of cardiacchannelopathies, IKr channel inhibition or QT prolongation; and anamount of a lysophosphatidylglycerol with a basic structure:

wherein R1 or R2 can be any even or odd-chain fatty acid, and R3 can beH, acyl, alkyl, aryl, amino acid, alkenes, alkynes, in the form of emptyliposomes adapted for oral administration effective to reduce or preventthe at least one cardiac channelopathies, IKr channel inhibition or QTprolongation caused by the drug, wherein the lysophosphatidylglycerolincludes at least one of a lysophosphatidylcholine,lauroyl-lysophosphatidylcholine, myristoyl-lysophosphatidylcholine,palmitoyl-lysophosphatidylcholine, stearoyl-lysophosphatidylcholine,arachidoyl-lysophosphatidylcholine, oleoyl-lysophosphatidylcholine,linoleoyl-lysophosphatidylcholine, linolenoyl-lysophosphatidylcholine orerucoyl-lysophosphatidylcholine.
 11. The composition of claim 10,wherein the liposome or liposome precursor are selected from at leastone or 1-Myristoyl-2-Hydroxy-snGlycero-3-Phosphocholine (DMPC),1,2-Dimyristoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DMPG), DMPC/DMPG,1-myristoyl-2-hydroxy-sn-glycero-3-phospho-(1′-rac-glycerol) (LysoPG),or 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine (LysoPC).
 12. Thecomposition of claim 10, wherein the short chain fatty acid is up to 5carbons, a medium chain is 6 to 12 carbons, a long chain is 13-21carbons and a very long chain fatty acid is greater than 22 carbons,including both even and odd chain fatty acids.
 13. The composition ofclaim 10, wherein the short chain fatty acid has 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 35, 40, 45, 50, 55 or more carbons, which are saturated orunsaturated.
 14. The composition of claim 10, wherein the cardiacchannelopathy or the condition resulting from the irregularity oralteration in the cardiac pattern is inhibition of an ion channelresponsible for the delayed-rectifier K+ current in the heart,polymorphic ventricular tachycardia, prolongation of the QTc, LQT2,LQTS, or torsades de pointes.
 15. The composition of claim 10, whereinthe composition is used for the treatment or prevention of prolongationof the IKr channel inhibition or QT prolongation induced byadministration of one or more drugs used in the treatment of cardiac,allergic, or cancer related disease.
 16. The composition of claim 10,wherein the one or more active agents is selected from at least one ofcrizotinib, nilotinib, terfenadine, astemizole, gripafloxacin,terodilene, droperidole, lidoflazine, levomethadyl, sertindoyle orcisapride.
 17. The composition of claim 10, wherein the active agent ordrug is provided enterally, parenterally, intravenously,intraperitoneally, or orally.
 18. The composition of claim 10, whereinthe drug is selected from Albuterol (salbutamol), Alfuzosin, Amantadine,Amiodarone, Amisulpride, Amitriptyline, Amoxapine, Amphetamine,Anagrelide, Apomorphine, Arformoterol, Aripiprazole, Arsenic trioxide,Astemizole, Atazanavir, Atomoxetine, Azithromycin, Bedaquiline,Bepridil, Bortezomib, Bosutinib, Chloral hydrate, Chloroquine,Chlorpromazine, Ciprofloxacin, Cisapride, Citalopram, Clarithromycin,Clomipramine, Clozapine, Cocaine, Crizotinib, Dabrafenib, Dasatinib,Desipramine, Dexmedetomidine, Dexmethylphenidate, Dextroamphetamine(d-Amphetamine), Dihydroartemisinin+piperaquine, Diphenhydramine,Disopyramide, Dobutamine, Dofetilide, Dolasetron, Domperidone, Dopamine,Doxepin, Dronedarone, Droperidol, Ephedrine, Epinephrine (Adrenaline),Eribulin, Erythromycin, Escitalopram, Famotidine, Felbamate,Fenfluramine, Fingolimod, Flecainide, Fluconazole, Fluoxetine,Formoterol, Foscarnet, Fosphenytoin, Furosemide (Frusemide),Galantamine, Gatifloxacin, Gemifloxacin, Granisetron, Halofantrine,Haloperidol, Hydrochlorothiazide, Ibutilide, Iloperidone, Imipramine(melipramine), Indapamide, Isoproterenol, Isradipine, Itraconazole,Ivabradine, Ketoconazole, Lapatinib, Levalbuterol (levsalbutamol),Levofloxacin, Levomethadyl, Lisdexamfetamine, Lithium, Mesoridazine,Metaproterenol, Methadone, Methamphetamine (methamfetamine),Methylphenidate, Midodrine, Mifepristone, Mirabegron, Mirtazapine,Moexipril/HCTZ, Moxifloxacin, Nelfinavir, Nicardipine, Nilotinib,Norepinephrine (noradrenaline), Norfloxacin, Nortriptyline, Ofloxacin,Olanzapine, Ondansetron, Oxytocin, Paliperidone, Paroxetine,Pasireotide, Pazopanib, Pentamidine, Perflutren lipid microspheres,Phentermine, Phenylephrine, Phenylpropanolamine, Pimozide, Posaconazole,Probucol, Procainamide, Promethazine, Protriptyline, Pseudoephedrine,Quetiapine, Quinidine, Quinine sulfate, Ranolazine, Rilpivirine,Risperidone, Ritodrine, Ritonavir, Roxithromycin, Salmeterol,Saquinavir, Sertindole, Sertraline, Sevoflurane, Sibutramine,Solifenacin, Sorafenib, Sotalol, Sparfloxacin, Sulpiride, Sunitinib,Tacrolimus, Tamoxifen, Telaprevir, Telavancin, Telithromycin,Terbutaline, Terfenadine, Tetrabenazine, Thioridazine, Tizanidine,Tolterodine, Toremifene, Trazodone, Trimethoprim-Sulfa, Trimipramine,Vandetanib, Vardenafil, Vemurafenib, Venlafaxine, Voriconazole,Vorinostat, or Ziprasidone.